Safety, Pharmacokinetics, and Pharmacodynamics of Cyclodextrin Itraconazole in Pediatric Patients with Oropharyngeal Candidiasis

Groll, Andreas H.; Wood, Lauren V.; Roden, Maureen; Mickiene, Diana; Chiou, Christine C.; Townley, Ellen; Dad, Luqman; Piscitelli, Stephen C.; Walsh, Thomas J.

doi:10.1128/aac.46.8.2554-2563.2002

Cited by 118 publications

(73 citation statements)

References 35 publications

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“…Although investigation of the pharmacokinetic profile of a drug in children is often delayed during the drug development process, results have been published of studies examining the pharmacokinetics in pediatric patients of currently marketed azole antifungals, such as itraconazole (7,12,25), fluconazole (3,15,16,26), and voriconazole (29). Pharmacokinetic profiles for itraconazole are inconsistent between pediatric patients and adults, and some pharmacokinetic parameters of fluconazole and voriconazole appear to differ between children and adults.…”

mentioning

confidence: 99%

Posaconazole Plasma Concentrations in Juvenile Patients with Invasive Fungal Infection

Krishna¹,

Sansone-Parsons²,

Martinho³

et al. 2007

Antimicrob Agents Chemother

147

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Posaconazole is an orally bioavailable triazole antifungal agent for the treatment and prophylaxis of invasive fungal infection. We evaluated plasma posaconazole concentration data from juvenile (younger than 18 years; n ‫؍‬ 12) and adult (18 to 64 years; n ‫؍‬ 194) patients who participated in a multicenter, phase 3, open-label study that assessed the efficacy and safety of posaconazole treatment for persons who were intolerant of or had invasive fungal infection refractory to standard antifungal therapies. With the exception of one juvenile patient who received 400 mg/day as a divided dose on the day of sample collection, all patients received posaconazole at 800 mg/day as an oral suspension in divided doses. Plasma samples were analyzed through a validated liquid chromatographic-tandem mass spectrometric method with a lower limit of quantitation of 1 ng/ml. Because plasma posaconazole concentrations are relatively constant at steady state, the average of all plasma concentrations (C av ) for each patient was calculated to provide a single steady-state plasma posaconazole concentration. A blinded data review committee reviewed all treatment outcomes. Variable posaconazole plasma concentrations were observed within both the juvenile and adult populations. Mean (median [range]) C av values for juvenile and adult patients were 776 ng/ml (579 ng/ml [85.3 to 2,891 ng/ml]) and 817 ng/ml (626 ng/ml [0 to 3,710 ng/ml]), respectively. Overall success rates and adverse event profiles were comparable. In conclusion, posaconazole concentrations in plasma were similar for juvenile and adult patients, suggesting that clinical outcomes are expected to be similar in adults and children with refractory invasive fungal infection.

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mentioning

confidence: 99%

Posaconazole Plasma Concentrations in Juvenile Patients with Invasive Fungal Infection

Krishna¹,

Sansone-Parsons²,

Martinho³

et al. 2007

Antimicrob Agents Chemother

147

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“…In addition, the half-life of azole is slightly prolonged in elderly people compared to the middle aged (224) and terbinafine AUC values are higher in the elderly than in young adults (193). Pharmacokinetics of itraconazole in elderly (116) and pediatric patients do not appear to be different (103); lower plasma concentrations in children and longer half times in elderly individuals have been observed in preliminary studies (58,116). The pharmacokinetics of terbinafine are similar in elderly and young subjects (134).…”

Section: Agementioning

confidence: 63%

“…The main metabolic pathways of itraconazole are oxidations and N-dealkylation (116) with CYP3A4, resulting in the formation of several metabolites, including the major metabolite, hydroxyitraconazole. In addition, barbiturates, carbamazepine, phenytoin, and rifampin, known CYP3A4 inducers, accelerate the metabolism of ketoconazole, itraconazole, and miconazole, and, to a lesser extent, fluconazole (2); antiretroviral protease inhibitors, such as ritonavir, are CYP3A4 substrates and reduce the clearance of itraconazole in pediatric patients (103). Particularly for fluconazole, coadministration with rifampin decreased the AUC and half-life of the antifungal (2).…”

Section: Metabolismmentioning

confidence: 99%

“…The clinical outcome is dependent on factors that include host defenses, the virulence of the fungal pathogen, and drug efficacy/toxicity, as well as drug interactions (148,277). Pharmacokinetic studies of antifungal agents have shown variability of at least 50% between individuals (45,49,101,103,192,206). For instance, interindividual variability in voriconazole plasma levels ranges from 74% to 100% (121).…”

Section: Introductionmentioning

confidence: 99%

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Human Pharmacogenomic Variations and Their Implications for Antifungal Efficacy

2006

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SUMMARY Pharmacogenomics is defined as the study of the impacts of heritable traits on pharmacology and toxicology. Candidate genes with potential pharmacogenomic importance include drug transporters involved in absorption and excretion, phase I enzymes (e.g., cytochrome P450-dependent mixed-function oxidases) and phase II enzymes (e.g., glucuronosyltransferases) contributing to metabolism, and those molecules (e.g., albumin, A1-acid glycoprotein, and lipoproteins) involved in the distribution of antifungal compounds. By using the tools of population genetics to define interindividual differences in drug absorption, distribution, metabolism, and excretion, pharmacogenomic models for genetic variations in antifungal pharmacokinetics can be derived. Pharmacogenomic factors may become especially important in the treatment of immunocompromised patients or those with persistent or refractory mycoses that cannot be explained by elevated MICs and where rational dosage optimization of the antifungal agent may be particularly critical. Pharmacogenomics has the potential to shift the paradigm of therapy and to improve the selection of antifungal compounds and adjustment of dosage based upon individual variations in drug absorption, metabolism, and excretion.

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“…Our study may also be relevant for humans. HP-b-CD is used as excipient for oral and parenteral administration of several pharmaceutical formulations approved for use in humans, including children (Groll et al 2002;Willems et al 2001). Some of the administered parenteral HP-b-CD dosages (e.g.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Parenteral Administration of 2-Hydroxypropyl-β-Cyclodextrin Causes Bone Loss

Kantner

Erben

2012

Toxicol Pathol

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Cyclodextrins are oligosaccharides which are used in the pharmaceutical industry and research as vehicles for application of apolar substances such as steroids. The aim of this study was to examine the long-term effects of parenteral administration of 2-hydroxypropyl-b-cyclodextrin (HP-b-CD) on bone. Sham-operated (SHAM) or ovariectomized (OVX) adult rats were subcutaneously injected with physiological saline, 50, or 200 mg/kg HP-b-CD daily. After 4 months, body weight in OVX rats and uterine weight in SHAM rats were significantly lower after administration of 200 mg/ kg HP-b-CD, relative to vehicle controls. At 200 mg/kg, HP-b-CD was hepatotoxic as measured by increased serum transaminases, and reduced serum albumin. Moreover, 200 mg/kg HP-b-CD led to decreased vertebral and tibial bone mineral density (BMD), and to cortical thinning at the tibial shaft. Bone loss in HP-b-CD-treated rats was associated with increased bone resorption as measured by increased renal deoxypyridinoline excretion. Although 50 mg/kg HP-b-CD was devoid of overt signs of organ toxicity and did not impair BMD, bone resorption was already increased. In summary, subcutaneous long-term administration of HP-b-CD at a daily dose of 200 mg/kg led to increased bone resorption and subsequent bone loss. Minor alterations in bone metabolism were also seen at 50 mg/kg.

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Safety, Pharmacokinetics, and Pharmacodynamics of Cyclodextrin Itraconazole in Pediatric Patients with Oropharyngeal Candidiasis

Cited by 118 publications

References 35 publications

Posaconazole Plasma Concentrations in Juvenile Patients with Invasive Fungal Infection

Posaconazole Plasma Concentrations in Juvenile Patients with Invasive Fungal Infection

Human Pharmacogenomic Variations and Their Implications for Antifungal Efficacy

Long-Term Parenteral Administration of 2-Hydroxypropyl-β-Cyclodextrin Causes Bone Loss

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